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BACKGROUND/AIMS

The role of von Willebrand factor (VWF) in the treatment of hemophilia A with inhibitors is being extensively studied. Several authors described the presence of VWF in coagulation factor VIII (FVIII) concentrates to be beneficial due to its protective effect against inhibitors. This study was aimed to evaluate the differences of FVIII in vivo recovery between FVIII concentrates –containing or not VWF– in the presence of human inhibitors using a mouse model of hemophilia A.

MATERIAL AND METHODS

In vivo FVIII recovery was evaluated in a severe hemophilia A mice model (FVIIInull E16 KO).

Different FVIII therapeutic concentrates (plasma-derived FVIII/VWF complex [pdFVIII/VWF], recombinant [rFVIII] and isolated pdFVIII) were used as FVIII source. In addition, mice were treated with the same FVIII concentrates previously mixed with therapeutic pdVWF concentrate (rFVIII+pdVWF and pdFVIII+pdVWF) in 1IU:1IU ratio. Inhibitor IgG was purified from a pool of hemophilic plasmas with inhibitors (Technoclone) using protein G Sepharose chromatography (GE Healthcare). This pool contains antibodies reacting against both Heavy and Light Chain of FVIII.

After 5 min post-inhibitor infusion the titer obtained was 3.2±0.4 BU/ml (n=6). Also, in the absence of inhibitor, basal levels of FVIII:C recovery in FVIIInull mice was similar for all FVIII concentrates, with values ranging from 107% to 124% (n=6) (see Figure 3). In contrast, in the presence of inhibitors the FVIII:C recovery in the same model was higher for VWF containing FVIII concentrates (71.1±17.4% for pdFVIII/VWF; n=6) when compared to concentrates composed of isolated FVIII (31.4±9.9% for rFVIII n=5 and 25.0±2.7% for pdFVIII n=5). When the isolated FVIII products were premixed with pdVWF prior to infusion, the FVIII recovery was only partially restored (67.1±15.1% for rFVIII+pdVWF n=6 and 45.2±8.8% for pdFVIII+pdVWF n=6) (See Figure 4). The FVIII:C recovery data were analyzed using a Student’s t-test. Statistical significance was set at p<0.05.